Irinotecan hydrochloride, (S)-4,11-diethyl-3,4,12,14-tetrahydro-4-hydroxy-3,14-dioxo-1H-pyrano[3′,4′:6,7]-indolizino[1,2-b]quinolin-9-yl [1,4′-bipiperidine]-1′-carboxylate hydrochloride or 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin hydrochloride, having the formula I
is a camptothecin analog and topoisomerase I inhibitor. Its trihydrate form has been approved in 1996 in the United States for the treatment of colon cancer, but it is also of interest for treatment of other cancers, such as cancers of the lung, the stomach and the pancreas.
Irinotecan is usually prepared semisynthetically from natural camptothecin, which is extracted from a Chinese tree, Camptotheca acunzinata. U.S. Pat. No. 4,604,463 describes several camptothecin derivatives, including irinotecan, its pharmaceutically acceptable salts and preparation thereof starting from natural camptothecin. U.S. Pat. No. 6,121,451 discloses intermediates and process for the synthesis of camptothecin derivatives, e.g. irinotecan hydrochloride, including synthetic route to starting material, 7-ethyl-10-hydroxy camptothecin.
Sawada et al., Chem. Pharm. Bull. 39(6), 1446-1454 (1991), describes the preparation of irinotecan hydrochloride trihydrate from natural camptothecin in five steps and about 20% of overall yield.
Natural camptothecin contains impurities, which are difficult to remove. The purification by chromatographic methods is mentioned e.g. in U.S. Pat. No. 4,473,692, where 7-ethyl-10-hydroxycamptothecin is made from 7-ethylcamptothecin-1-oxide. The availability of natural camptothecin may also limit the production of irinotecan.
Synthetically can be obtained a product, where there are less impurities and they are easier to remove. In U.S. Pat. No. 6,121,451 there has been presented a synthetic route to 7-ethyl-10-hydroxy camptothecin. The obtained product has been used without purification for the preparation of irinotecan. Crude irinotecan so produced is purified by a chromatographic method, which is not applicable in industrial scale. WO 02/066416 describes the method for the preparation of 7-ethyl-10-hydroxy camptothecin by a reaction of 4-ethyl-7,8-dihydro-4-hydroxy-1H-pyrano[3,4-f]indolizine-3,6,10(4H)-trione and 1-(2-amino-5-hydroxyphenyl)-propan-1-one in toluene:AcOH, 1:1, whereafter the reaction mixture is condensed, toluene is added, and the mixture is condensed again. The residue is slurried in acetone, filtered and washed with acetone. The product was achieved as black solid. Yield was 89%, purity 97.7%. Wall et al. have described in general terms the preparation of racemic 7-ethyl-10-hydroxycamptothecin in U.S. Pat. No. 4,894,456 and enantiomerically enriched forms in U.S. Pat. No. 5,053,512, but no examples for the preparation of 7-ethyl-10-hydroxycamptothecin are given.
For the reasons above there exists a need to produce 7-ethyl-10-hydroxycamptothecin synthetically by industrially applicable method to ensure the availability of high quality raw material for the preparation of irinotecan.
Now the inventor has noticed that pure 7-ethyl-10-hydroxy camptothecin can be achieved in high yield, if higher reaction temperatures and faster heating to that temperature are used. The product can be isolated by crystallization, and pure product is achieved without recrystallization or other purification methods. Also, highly pure irinotecan using 7-ethyl-10-hydroxycamptothecin of the invention as a starting material can be obtained without specific purification methods.